This invention relates to compounds for overcoming resistance that a patient may build to therapeutics.
Treatment of many diseases can be severely limited by resistance to the chosen therapeutic drug. For example, chemotherapy, while generally an effective treatment against human cancerous diseases, is hampered when a patient becomes resistant to the chemotherapeutic. In one special form of drug resistance, called "Multidrug Resistance," the cell becomes resistant not only to the chemotherapeutic being administered, but to a wide range of structurally and functionally unrelated drugs simultaneously (see Ford et al., Pharmacological Reviews, 42:155-199, 1992).
The cause of multidrug resistance is the appearance of an integral glycoprotein in the plasma membrane of the targeted cell, e.g., a tumor cell (FIG. 1). The protein functions as a multidrug transporter, and is variously called MultiDrug-Resistance 1 protein (MDR1), P-glycoprotein (pleiotropic-glycoprotein), Pgp, or P-170. MDRl consists of 1280 amino acid residues, and contains 12 transmembrane segments and two nucleotide-binding domains. It strongly resembles prokaryotic and eukaryotic members of the so-called ABC (ATP Binding Cassette) transporters, or traffic ATPases (see Endicott et al., Annu. Rev. Biochem. 58:137-171, 1989; Higgins, Annu. Rev. Cell. Biol. 8:67-113, 1992).
MDR1 naturally functions to, and is highly expressed in tissues normally responsible for, extruding toxic materials and waste-products from cells (e.g., lung, kidney, and liver), and secretes hydrophobic compounds from exocrine or endocrine glands (Gottesman et al., J. Biol. Chem. 263:12163-12166, 1988; Higgins et al., supra). Consistent with its natural function, MDR1 catalyses an ATP-dependent extrusion of various cytotoxic drugs from the cell, e.g., vinca alkaloids, anthracyclines, and other natural antibiotics, thereby maintaining their cellular level at a subtoxic concentration. Thus, when expressed by tumor cells, MDR1 expels cytotoxic chemotherapeutic agents, and thus allows the tumor cell to survive anticancer treatments even at high drug doses. At the same time, "ordinary" cells, having no such extrusion mechanism, may receive a lethal drug exposure. Tumors developing from tissues normally expressing the MDR1 protein often show a primary drug resistance, while in other tumors a secondary drug resistance may develop after chemotherapy.
The phenomenon of multidrug resistance is not limited to tumor cells. MDR1 and its homologues are expressed in a wide variety of cell-types, including parasitic protozoa. Consequently, overexpression of a member of the MDR1 family of proteins creates obstacles to a wide variety of parasitic diseases, including malaria, African sleeping sickness, and others (Campbell et al., Chemotherapy of Parasitic Diseases, Plenum Press:NY, 1986; Henderson et al., Mol. Cell. Biol. 12:2855-65, 1992). MDR1 is also expressed by endothelial cells of human capillary blood vessels at the blood-brain barrier and blood-testis barrier (Ford et al. supra, at 159).
It is known that verapamil, a drug that blocks voltage-dependent calcium channels, stimulates the activity of MDR1-bound ATPase at a concentration of 1 to 20 .mu.M but inhibits it as a concentration above 100 .mu.M (Sarkadi et al. J. Biol. Chem. 267:4854-4858, 1992). While between these concentrations verapamil blocks the extrusion of antitumor drugs, its high toxicity severely limits its clinical use (Solary et al. Leukemia 5:592-597, 1991; Dalton et al. J. Clin. Oncology 7:415-418, 1989).
In SU-A-1544778, Golovina, T. N. et al describe the preparation of different peptides one of which, BOC-Leu-Tyr-OMe is structurally close to the peptides provided by the present invention. Nevertheless, no hints on the possible biological activity of said peptide are disclosed.